Rats exposed to repeated restraint stress (3 h of restraint on each of 3 days) lose weight during stress and do not return to the weight of nonstressed controls once stress ends. Others have reported that chronic stress raises the daily nadir of corticosterone release and increases the adrenal response to subsequent stress; therefore, we examined glucocorticoid release in rats that had been exposed to repeated restraint. Repeated restraint had no effect on the diurnal pattern of corticosterone or insulin release, measured 12 days after restraint had ended, indicating that the reduced weight of the rats is not associated with an elevated corticosterone-insulin ratio. In contrast, rats that had been exposed to repeated restraint, 12 days previously, showed a blunted corticosterone release during a second restraint stress, a normal response to the novel physiological stress of 2-deoxy glucose (2-DG) injection, but an exaggerated corticosterone response to the novel mild stress (MS) of either placement in a unfamiliar environment or an intraperitoneal injection of saline. Mice exposed to repeated restraint showed a similar hyperresponsiveness to novel MS, suggesting that repeated restraint lowers the threshold for stress-induced activation of the adrenal gland. MS caused a small, but significant, degree of hypophagia in rats that had been exposed to repeated restraint stress. Therefore, multiple aspects of the stress response may be exaggerated in these animals and contribute to the chronic reduction in body weight.